Objective: To explore molecular characteristics of endometrial endometrioid cancer according to The Cancer Genome Atlas (TCGA) based molecular classification of endometrial carcinomas and to confirm simple and clinically applicable surrogate methodologies in pathological practice. Methods: Two hundred and twenty-eight cases of endometrial endometroid adenocarcinomas (EnACs) collected from August 2001 to August 2017 from Peking University Health Science Center, Peking University Third Hospital were molecularly categorized by using Sanger sequencing for the exonuclease domain mutations (EDM) of POLE, and by immunohistochemistry for p53 and mismatch repair (MMR) proteins. The cohort was classified into polymerase-E exonuclease domain mutation (POLE EDM), mismatch repair deficiency (MMR-D), p53 abnormal (p53-abn) and p53 wild type (p53-wt) groups. The correlation between molecular subgroups and the clinical-pathological features including prognosis were analyzed. Results: The cohort was distributed as follows: 11(4.8%) POLE EDM, 47(20.6%) MMR-D, 9(4.0%) p53-abn and 161(70.6%) p53-wt. p53-wt subgroup patients demonstrated significantly higher lymph node metastasis (P=0.011) and more advanced stage (P=0.036) than those of somatic hypermutation group cases (POLE EDM and MMR-D). In the FIGO grade 2-3 EnACs cohort, TCGA molecular subtyping was significantly correlated with progression-free survival and overall survival (P=0.043). POLE EDM subgroup had the best survival, while p53-abn subgroup had the worst. Conclusions: Identification of POLE EDM and MMR-D subgroups provides independent and highly valuable prognostic information beyond established histological classification. Based on immunohistochemistry of MMR, p53 and POLE mutational analysis, this pragmatic molecular classification scheme can be served as a reliable surrogate for TCGA molecular classification, which has potential to be used routinely in Chinese pathological practice.
目的： 依据"癌症基因组图谱（The Cancer Genome Atlas，TCGA）子宫内膜癌分子分型"策略，初步探索形态学符合子宫内膜样癌病例的分子特征及分子分型的可行性和合理流程。 方法： 利用免疫组织化学染色和Sanger测序，检测北京大学医学部北京大学第三医院2001年8月至2017年8月228例子宫内膜样癌的POLE基因突变状态及错配修复（MMR）蛋白、p53蛋白表达，并将其划分为POLE核酸外切酶域突变型（POLE exonuclease domain mutations，POLE EDM）、MMR缺陷型（MMR-deficient，MMR-D）、p53突变型（p53 abnormal，p53-abn）和p53野生型（p53 wild-type，p53-wt）4个分子亚型，分析各分子分型与临床病理特征及预后的相关性。 结果： 该组病例中POLE EDM亚型11例（4.8%）、MMR-D亚型47例（20.6%）、p53-abn亚型9例（4.0%）和p53-wt亚型161例（70.6%）。与具有高频体细胞突变POLE EDM和MMR-D亚型患者相比，p53-wt亚型的淋巴结转移率及临床分期显著增高（P=0.011，0.036），但各分子亚型与其他临床病理参数之间差异无统计学意义（P>0.05）。在中-低分化内膜样癌患者中，4种分子分型的无疾病进展生存期和总生存期差异具有统计学意义（P=0.043），其中POLE EDM预后最好，p53-abn预后最差。 结论： 在子宫内膜样癌中，POLE EDM和MMR-D的识别具有较高的临床实用价值，是分子分型中最有价值的分流指标。基于MMR、p53蛋白的免疫组织化学染色和POLE基因突变检测的分型策略能够较好模拟"TCGA子宫内膜癌分子分型"，在国内病理科常规开展具有可行性和合理性。.
Keywords: Carcinoma, endometrioid; Molecular typing; Pathology, clinical; Prognosis.